Recombinant DNA Advisory Committee - 2/10-11/92 
a positive impact on the disease might be possible. 
The original ADA protocol involved children who received PEG- ADA treatment and 
continued to have significant, persisting immune deficiency. The initial protocol had three 
treatment parts: (1) to insert the ADA gene, expand this population in culture for one to 
two weeks, and then infuse (the early reinfusion phase); (2) to select only ADA positive 
gene corrected cells to be included in the infused population; and (3) to progressively 
increase the dose of infused cells to see if PEG-ADA treatment could be discontinued. 
PEG-ADA treatment has been continued throughout the first two parts of the treatment 
program. 
Dr. Blaese stated that the investigators intended to abandon the last two parts of the 
treatment protocol, primarily because Phase I had been so successful and the patients were 
self-selecting the genetically corrected cells. Therefore, the length of survival for the cells 
that were not genetically corrected was short, which was presumably due to their ADA 
deficiency, but the genetically corrected T lymphocytes persisted. 
Dr. Blaese noted that the current protocol, which requires peripheral T lymphocyte 
correction, is problematic in that there are thousands of different mature peripheral blood 
T lymphocytes and each may have different T lymphocyte receptor specificities. To 
achieve a positive impact on patients it is necessary to select and correct as many of those 
specificities as possible. Dr. Blaese cited two problems with this approach: (1) involves 
apheresing patients in order to obtain large numbers of lymphocytes; and (2) the 
repertoire in the peripheral blood is not stable. Patients make an immune response to 
those antigens that they are exposed; therefore, the relative distribution of the repertoire is 
constantly changing. The repertoire contained within the blood samples varies over time; 
therefore, samples have to be taken continuously to gather as much information about the 
repertoire as possible. 
Dr. Blaese described the treatment of ADA deficient patients to date and the results. The 
first patient, a four-year-old female, was diagnosed with profound T-lymphopenia at about 
two years of age. The patient was initially treated with PEG-ADA and initially showed 
improvement in her lymphocyte count. However, during the second year of treatment, 
despite increased enzyme dosages, lymphopenia developed again. This patient entered 
into this protocol in September 1990. Objective measures of immune function showed 
profound immune deficiency and no cellular immune function. The patient was anergic, 
had no positive skin tests, and could not make specific antibodies. 
Dr. Blaese reported that the patient was infused with an initial dose of lxlO 9 total gene 
corrected peripheral blood T lymphocytes. Throughout treatment, the efficiency of gene 
transfer ranged from 2 to 10%, which indicated that 90 to 95% of the infused cells were 
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Recombinant DNA Research, Volume 15 
